ASSURING EFFECTIVE ANTIMALARIAL TREATMENT:
A PLAN FOR MOVING FORWARD
ASSURING EFFECTIVE ANTIMALARIAL TREATMENT:
A PLAN FOR MOVING FORWARD
CAROL HOPKINS SIBLEYATELIER PALUDISME
MADAGASGARMARCH 19, 2007
CAROL HOPKINS SIBLEYATELIER PALUDISME
MADAGASGARMARCH 19, 2007
WHAT ARE THE PRACTICAL CONSEQUENCES?WHAT ARE THE PRACTICAL CONSEQUENCES?
ESTIMATED ALL- CAUSE CHILD MORTALITYSNOW, TRAPE AND MARSH, 2001
ESTIMATED ALL- CAUSE CHILD MORTALITYSNOW, TRAPE AND MARSH, 2001
RESISTANCE TO THREECOMMON
INEXPENSIVE WELL TOLERATED
DRUGS HAS EVOLVED
RESISTANCE TO THREECOMMON
INEXPENSIVE WELL TOLERATED
DRUGS HAS EVOLVED
• CHLOROQUINE
• SULFADOXINE-PYRIMETHAMINE
• MEFLOQUINE
• CHLOROQUINE
• SULFADOXINE-PYRIMETHAMINE
• MEFLOQUINE
HOW DO WE DEFINE DRUG RESISTANCEHOW DO WE DEFINE DRUG RESISTANCE
• IN VIVODOES A PROPERLY TREATED PATIENT RECOVER?
• IN VITROHOW SENSITIVE IS A PARASITE ISOLATE
TO DRUG ?• MOLECULAR
ARE MUTATIONS ASSOCIATED WITH RESISTANCE COMMON IN THE REGION?
• PHARMACOKINETICSDID THE PATIENT HAVE A CORRECT LEVEL OF
DRUG IN THE BLOOD?
• IN VIVODOES A PROPERLY TREATED PATIENT RECOVER?
• IN VITROHOW SENSITIVE IS A PARASITE ISOLATE
TO DRUG ?• MOLECULAR
ARE MUTATIONS ASSOCIATED WITH RESISTANCE COMMON IN THE REGION?
• PHARMACOKINETICSDID THE PATIENT HAVE A CORRECT LEVEL OF
DRUG IN THE BLOOD?
PATIENT RESPONSE TO TREATMENT FOLLOW UP 28 DAYS ++
SYMPTOMS AND PARASITES GONEALL 28 DAYS
SYMPTOMS REAPPEAR WITHIN 3 DAYSWITHIN 28 DAYS
PARASITES ONLY REAPPEARWITHIN 28 DAYS
PATIENT RESPONSE TO TREATMENT FOLLOW UP 28 DAYS ++
SYMPTOMS AND PARASITES GONEALL 28 DAYS
SYMPTOMS REAPPEAR WITHIN 3 DAYSWITHIN 28 DAYS
PARASITES ONLY REAPPEARWITHIN 28 DAYS
HOW DO WE MONITOR DRUG EFFICACY?
HOW DO WE MONITOR DRUG EFFICACY?
ETF
LPF
LTF
ACPR
WHAT FACTORS INFLUENCE THE CLINICAL RESPONSE?
WHAT FACTORS INFLUENCE THE CLINICAL RESPONSE?
• PRIOR EXPOSURE• PRIOR EXPOSURE
• POSSIBILITY OF REINFECTION• POSSIBILITY OF REINFECTION
• NUTRITIONAL STATUS• NUTRITIONAL STATUS
• OTHER INFECTIONS• OTHER INFECTIONS
• OTHER DRUG USE• OTHER DRUG USE
HOW IS THIS INFORMATION USED?HOW IS THIS INFORMATION USED?
WHO GUIDELINES- 2006
>15% CLINICAL/PARASTIOLOGICAL FAILURES-
CHANGE TO NEW DRUG
WHO GUIDELINES- 2006
>15% CLINICAL/PARASTIOLOGICAL FAILURES-
CHANGE TO NEW DRUG
WHAT HAVE WE LEARNED ABOUT THE EVOLUTION OF DRUG RESISTANCE?
WHAT HAVE WE LEARNED ABOUT THE EVOLUTION OF DRUG RESISTANCE?
• TWO IMPORTANT PHASES OF RESISTANCE• SELECTION OF RESISTANCE• PROPAGATION OF RESISTANCE
• TWO IMPORTANT PHASES OF RESISTANCE• SELECTION OF RESISTANCE• PROPAGATION OF RESISTANCE
FOCI OF CLINICAL RESISTANCE ARISE RELATIVELY RARELY TO CQ AND SP
1978
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1978
1981
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1982
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1978
1983
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1984
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1985
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1986
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1987
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1988
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
1989
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA
ADAPTED FROM CHARMOT ET AL, 1991
ADAPTED FROM CHARMOT ET AL, 1991
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
HUMAN MIGRATION
IS KEY TO
RESISTANCE SPREAD
TREATMENT FAILURE = RESISTANCE?TREATMENT FAILURE = RESISTANCE?
DOSE OF DRUG ADEQUATE?DOSE OF DRUG ADEQUATE?
YESYESNONO
MARKERS OF DRUG
RESISTANCE?
MARKERS OF DRUG
RESISTANCE?
HIGHER THANSTANDARD?
HIGHER THANSTANDARD?
GENETIC ANALYSIS
OF PARASITE
GENETIC ANALYSIS
OF PARASITE
IN VITRO RESPONSE
OF PARASITES TO DRUGS
IN VITRO RESPONSE
OF PARASITES TO DRUGS
MAY NOT BE
RESISTANCE
MAY NOT BE
RESISTANCE
RESISTANCE?RESISTANCE?
INFECTED BLOOD + PBS
CF11 column
RESUSPEND IN MEDIUM AND SERUM
INCUBATE 37 O C 24-36 H
MEASURE GROWTH
DRUG CONCENTRATION
ABCDEFGHPA
TIEN
T IS
OLA
TE
CALCULATEDRUG RESPONSE
MEASUREMENT OF PARASITE DRUG SENSITIVITY IN VITRO
MEASUREMENT OF PARASITE DRUG SENSITIVITY IN VITRO
AVOIDS MAJORHOST FACTORS:
IMMUNITYNUTRITION
0102030405060708090
100110120
0 1E -9 1E -8 1E -7 1E -6 1E -5 [PYRIMETHAMINE
REL
ATIV
E G
RO
WTH
Y5D3S108S108NS108N + N51IF.S. 7 E4F.S. C1
IC50 3.4 x 10-8 IC50 4 x 10-7 IC50 9 x 10-7
DRUG RESPONSE OF FIELD SAMPLES SCREENED BY GROWTH IN VITRO
DRUG RESPONSE OF FIELD SAMPLES SCREENED BY GROWTH IN VITRO
MOLECULAR MARKERS OF DRUG RESISTANCEMOLECULAR MARKERS OF DRUG RESISTANCE
CQ Pfcrt SNPsPfmdr1 SNPs
SP Pfdhfr SNPsPfdhps SNPs
MEF Pfmdr1 COPY NUMBER
CQ Pfcrt SNPsPfmdr1 SNPs
SP Pfdhfr SNPsPfdhps SNPs
MEF Pfmdr1 COPY NUMBER
ONE GENE IS NECESSARY FOR CQ-RIn P. falciparum
ONE GENE IS NECESSARY FOR CQ-RIn P. falciparum
But probably is not sufficient! But probably is not sufficient!
PYRS Asn Cys Ser Ile
51 59 Pf DHFR 108 164
Asn Cys ASN Ile
ILE Cys ASN Ile
ILE ARG ASN Ile
DHFR MUTATIONS THAT CONFER PYRIMETHAMINE RESISTANCE IN FIELD ISOLATES
DHFR MUTATIONS THAT CONFER PYRIMETHAMINE RESISTANCE IN FIELD ISOLATES
ILE ARG ASN LEU
PYRR
Mugittu et al 2004
MOLECULAR MARKERS CAN ASSESS PARASITE DRUG RESISTANCE
MOLECULAR MARKERS CAN ASSESS PARASITE DRUG RESISTANCE
DHFRAND DHPS
ALLELESTANZANIA2002-2004
DHFRAND DHPS
ALLELESTANZANIA2002-2004
TRIPLE MUTANT dhfrDOUBLE MUTANT dhps
TRIPLE MUTANT dhfrDOUBLE MUTANT dhps
Pfmdr1 COPY NUMBER IS MARKER OF MEFLOQUINER
Pfmdr1 COPY NUMBER IS MARKER OF MEFLOQUINER
MQR
MQS
1.0
1.1
2.0
2.3
Wongsrichanalai C., 2005
MOLECULAR MARKERS OR
IN VITRO ANALYSIS GOOD SURROGATES
TO PREDICT CLINICAL TREATMENT FAILURE?
MOLECULAR MARKERS OR
IN VITRO ANALYSIS GOOD SURROGATES
TO PREDICT CLINICAL TREATMENT FAILURE?
KEY QUESTION:KEY QUESTION:
STUDIES IN PATIENTS AREEXPENSIVE
ANDTIME CONSUMING
STUDIES IN PATIENTS AREEXPENSIVE
ANDTIME CONSUMING
Mugittu et al 2004
MOLECULAR MARKERS CAN ASSESS PARASITE DRUG RESISTANCE
MOLECULAR MARKERS CAN ASSESS PARASITE DRUG RESISTANCE
DHFRAND DHPS
ALLELESTANZANIA2002-2004
DHFRAND DHPS
ALLELESTANZANIA2002-2004
TRIPLE MUTANT dhfrDOUBLE MUTANT dhps
CLINICAL FAILURE
MOLECULAR MARKERS OF SP RESISTANCECORRLEATE WITH CLINICAL FAILURE
MOLECULAR MARKERS OF SP RESISTANCECORRLEATE WITH CLINICAL FAILURE
0 0.1 0.2 0.3 0.4PREVALENCE OF "TRIPLE/DOUBLE"
0
0.2
0.4
0.6
0.8
1.0C
LIN
ICAL
FA
ILU
RE
Observed-14Observed-28Observed-42Fit-14Fit-28Fit-42
0.5 0.6
PREV
ALE
NC
EO
F R
ESIS
TAN
T P[
AR
ASI
TES
(%)
10%
50%
100%
90%
90-93 93-95 95-97 97-99 00-02UNTIL LATE 80s
PM/SD INTRODUCED KILIFI, KENYA
10%
20%
30%
50%
HOW CAN WE FIT THIS TOGETHER?HOW CAN WE FIT THIS TOGETHER?
TR
IPL
E M
UT
AN
TS
DH
FR
PM R
ESIS
TANCE
in vi
tro
50%
30%
20%
10%
60%
70%
XX
X
% T
RIPL
E M
UTAN
TS
PM/SD RESISTANCEin vi
vo
DATA FROMALEXIS NZILA
EDWARD MBERU KAMAUCAROL SIBLEY
EARLY WARNINGS OF CLINICAL FAILURE
WHAT HAVE WE LEARNED?WHAT HAVE WE LEARNED?• RESISTANCE ARISES RARELY, BUT
SPREADS RELATIVELY QUICKLY
• CLINICAL TREATMENT FAILURE IS THE LAST STEP IN A LONG SERIES OF CHANGES
• EARLY WARNING OF RESISTANCE• SLOWER TIME TO CLEAR PARASITES
• IN VITRO INCREASES IN IC50 VALUE
• INCREASING PREVALENCE OF “RESISTANT” ALLELES
• RESISTANCE ARISES RARELY, BUT SPREADS RELATIVELY QUICKLY
• CLINICAL TREATMENT FAILURE IS THE LAST STEP IN A LONG SERIES OF CHANGES
• EARLY WARNING OF RESISTANCE• SLOWER TIME TO CLEAR PARASITES
• IN VITRO INCREASES IN IC50 VALUE
• INCREASING PREVALENCE OF “RESISTANT” ALLELES
WHAT DATA ARE MISSING?WHAT DATA ARE MISSING?• SURVEILLANCE SPOTTY• REPORTS LONG AFTER FACT• SURVEILLANCE SPOTTY• REPORTS LONG AFTER FACT
BUT THIS IS IMPROVING RAPIDLY
1986
Charmot et al 1991
4-5 years6-7 years8 years
VERY LONGLAG
BETWEENSEEING
RESISTANCEAND
CHANGINGDRUG
POLICY
VERY LONGLAG
BETWEENSEEING
RESISTANCEAND
CHANGINGDRUG
POLICY
NEED FAR BETTER COORDINATION AMONG GROUPS INVOLVED IN RESISTANCE DETERMINATIONNEED FAR BETTER COORDINATION AMONG GROUPS INVOLVED IN RESISTANCE DETERMINATION
WE HAVE ALWAYS PLAYED CATCH UPWE HAVE ALWAYS PLAYED CATCH UP
FROM WHITE, 1999
AS DRUGS FAIL, WE CHRONICLE THE FAILURES
WE NEED COORDINATED, OPEN ACCESSDATABASE FROM ALL ENDEMIC AREASWE NEED COORDINATED, OPEN ACCESSDATABASE FROM ALL ENDEMIC AREAS
NEEDS TO CONNECT WITH ROUTINE SURVEILLANCE
• CONSOLIDATE RECENT DATA ON “OLD”DRUGS
• CREATE AND MAINTAIN AN OPEN ACCESS DATABASE OF RESISTANCE DATA WORLDWIDE
• CONSOLIDATE RECENT DATA ON “OLD”DRUGS
• CREATE AND MAINTAIN AN OPEN ACCESS DATABASE OF RESISTANCE DATA WORLDWIDE
• WHERE DID RESISTANCE ARISE?
• OVER WHAT ROUTES DID SPREAD OCCUR?
• HOW DO SURROGATE MARKERS RELATE TO CLINICAL OUTCOMES?
• WHERE DID RESISTANCE ARISE?
• OVER WHAT ROUTES DID SPREAD OCCUR?
• HOW DO SURROGATE MARKERS RELATE TO CLINICAL OUTCOMES?
WHAT MUST WE DO NOW?WHAT MUST WE DO NOW?
THINGS USED TO BE SIMPLE…THINGS USED TO BE SIMPLE…
CHLOROQUINESULFADOXINE/PYRIMETHAMINE
QUININEMEFLOQUINE
MEFLOQUINE/ARTESUNATE
CHLOROQUINESULFADOXINE/PYRIMETHAMINE
QUININEMEFLOQUINE
MEFLOQUINE/ARTESUNATE
2006
RESISTANCE TO OLD DRUGS…. CHANGE TO COMBINATION THERAPY
RESISTANCE TO OLD DRUGS…. CHANGE TO COMBINATION THERAPY
2003
MANY ACTs ARE IN USE OR IN TRIALMANY ACTs ARE IN USE OR IN TRIAL• ARTESUNATE-MEFLOQUINE
• ARTEMETHER-LUMEFANTRINE
• ARTESUNATE-AMODIAQUINE
• DIHYDROARTEMISININ-PIPERAQUINE
• CHLORPROGUANIL-DAPSONE-ARTESUNATE
• ARTESUNATE- SULFADOXINE-PYRIMETHAMINE
• ARTESUNATE-MEFLOQUINE
• ARTEMETHER-LUMEFANTRINE
• ARTESUNATE-AMODIAQUINE
• DIHYDROARTEMISININ-PIPERAQUINE
• CHLORPROGUANIL-DAPSONE-ARTESUNATE
• ARTESUNATE- SULFADOXINE-PYRIMETHAMINE
AND…..• CHLOROQUINE- SULFADOXINE-PYRIMETHAMINE
• AMODIAQUINE - SULFADOXINE-PYRIMETHAMINE
AND…..• CHLOROQUINE- SULFADOXINE-PYRIMETHAMINE
• AMODIAQUINE - SULFADOXINE-PYRIMETHAMINE
ACTs CURRENTLY EFFECTIVE, BUT……..
ACTs CURRENTLY EFFECTIVE, BUT……..
HOW CAN WE SUSTAIN MAXIMUM
USEFUL THERAPEUTIC LIFE OF ACTs?
HOW CAN WE SUSTAIN MAXIMUM
USEFUL THERAPEUTIC LIFE OF ACTs?
HOW CAN WE STAY AHEAD OF THE
EVOLUTIONARY CURVE?
HOW CAN WE STAY AHEAD OF THE
EVOLUTIONARY CURVE?
NETWORK MUST BE PROSPECTIVENETWORK MUST BE PROSPECTIVE
• CURRENT TOOLS ARE ADEQUATE
• MANY WELL PLACED SENTINAL SITES
• REAL TIME REPORTING MORE COMMON
• NEW INITIATIVES WITH COMPLEMENTARY OBJECTIVES
• CURRENT TOOLS ARE ADEQUATE
• MANY WELL PLACED SENTINAL SITES
• REAL TIME REPORTING MORE COMMON
• NEW INITIATIVES WITH COMPLEMENTARY OBJECTIVES
• GLOBAL FUND REQUIREMENTS• ACT CONSORTIUM• IPTp• IPTi
• GLOBAL FUND REQUIREMENTS• ACT CONSORTIUM• IPTp• IPTi
CLINICAL DRUG
EFFICACY
PHARMACO-LOGICAL
ASSESSMENTIN VITRODRUG
ASSESSMENT
MOLECULARMARKERS
OF RESISTANCE
WORLD ANTIMALARIAL RESISTANCE NETWORK WORLD ANTIMALARIAL RESISTANCE NETWORK
CLINICAL DRUG
EFFICACY
CLINICAL DRUG
EFFICACY
PHARMACO-LOGICAL
ASSESSMENT
PHARMACOLOGICAL ASSESSMENT OF DRUGS
PHARMACOLOGICAL ASSESSMENT OF DRUGS
WAS THE DRUG LEVEL ADEQUATE?
WAS THE DRUG LEVEL ADEQUATE?
WHY DID THE PATIENT FAIL TREATMENT?
WHY DID THE PATIENT FAIL TREATMENT?
CLINICAL FAILURE WITH ADEQUATE DRUG
CLINICAL FAILURE WITH ADEQUATE DRUG
PRESUMPTIVE RESISTANT PARASITES
PRESUMPTIVE RESISTANT PARASITES
IN VITRO ANALYSISIN VITRO ANALYSIS
PATIENT ISOLATES WITH INCREASEDDRUG RESISTANCE IN VITRO
PATIENT ISOLATES WITH INCREASEDDRUG RESISTANCE IN VITRO
CANDIDATES FOR INTENSIVE GENETIC ANALYSIS
CANDIDATES FOR INTENSIVE GENETIC ANALYSIS
IDENTIFICATION OF LOCI ASSOCIATED WITH RESISTANCE TO EACH
PARTNER IN ACT
IDENTIFICATION OF LOCI ASSOCIATED WITH RESISTANCE TO EACH
PARTNER IN ACT
HOW TO MOVE TO EVIDENCE BASED DRUG USE
HOW TO MOVE TO EVIDENCE BASED DRUG USE
Don deSavigny and Fred BinkaDon deSavigny and Fred Binka
WE’RE HERE
WE NEED TO MOVE TO HERE
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